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Article: [Phosphorylation of Smurf2 at Thr249 by Erk5 regulates TGF-β signaling].

Iezaki, Takashi / Hinoi, Eiichi

Nihon yakurigaku zasshi. Folia pharmacologica Japonica

2021 Volume 156, Issue 5, Page(s) 271–274

Abstract: Vertebral bone and limb bone are formed by endochondral ossification, which is replaced with bone tissue by osteoblasts after cartilage formation. Bone growth is regulated by the balance between epiphyseal chondrocyte proliferation and ossification. We ... ...

Abstract	Vertebral bone and limb bone are formed by endochondral ossification, which is replaced with bone tissue by osteoblasts after cartilage formation. Bone growth is regulated by the balance between epiphyseal chondrocyte proliferation and ossification. We attempted to elucidate the mechanism of chondrocyte differentiation and maturation regulated by the Extracellular-signal-regulated kinase 5 (Erk5) signal. Erk5 is a serine/threonine kinase belonging to the mitogen-activated protein kinase (MAPK) family, which includes Erk1/2, JNK, and p38. Mesenchymal stem cell-specific Erk5-deficient mice exhibited the phenotype of deformities of the metatarsal bones, enlargement of the long bones in limbs, and overgrowth of cartilage tissue. Based on this result, we searched for factors that directly phosphorylate Erk5, and We demonstrated that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249 to activate its function and promotes ubiquitination-mediated degradation. The TGF-β-Smad signal suppresses the proliferation of many cells and regulates the production of extracellular matrix. Our findings may lead to the development of novel drugs targeting TGF-β associated diseases. In this paper, we investigated the function of Smurf2
MeSH term(s)	Animals ; Cell Differentiation ; Mice ; Mitogen-Activated Protein Kinase 7/genetics ; Mitogen-Activated Protein Kinase 7/metabolism ; Phosphorylation ; Transforming Growth Factor beta/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Transforming Growth Factor beta ; SMURF2 protein, human (EC 2.3.2.26) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; MAPK7 protein, human (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 7 (EC 2.7.11.24)
Language	Japanese
Publishing date	2021-09-01
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1097532-9
ISSN	1347-8397 ; 0015-5691
ISSN (online)	1347-8397
ISSN	0015-5691
DOI	10.1254/fpj.21029
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Article ; Online: [The Future of Osteoporosis Research and Treatment].

Hinoi, Eiichi / Arai, Kunizo

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2019 Volume 139, Issue 1, Page(s) 13–14

MeSH term(s)	Absorptiometry, Photon ; Animals ; Biomarkers/blood ; Biomarkers/urine ; Bone Density ; Bone Density Conservation Agents/administration & dosage ; Bone Resorption ; Humans ; Macrophage Colony-Stimulating Factor ; Mice ; Osteogenesis ; Osteoporosis/diagnosis ; Osteoporosis/prevention & control ; Osteoporosis/therapy ; RANK Ligand ; Research/trends
Chemical Substances	Biomarkers ; Bone Density Conservation Agents ; RANK Ligand ; Macrophage Colony-Stimulating Factor (81627-83-0)
Language	Japanese
Publishing date	2019-01-03
Publishing country	Japan
Document type	Journal Article
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.18-00154-F
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Article ; Online: Osteoblastgenic and Osteogenic Effects of KY-273 with CDK8/19 Inhibitory Activity in Bone Marrow Mesenchymal Stem Cells and Female Rats.

Yamamoto, Megumi / Shibata, Yui / Ito, Yuma / Fukui, Masaki / Kioka, Hikaru / Shoji, Yoshimichi / Kitao, Tatsuya / Shirahase, Hiroaki / Hinoi, Eiichi

Biological & pharmaceutical bulletin

2024 Volume 47, Issue 3, Page(s) 669–679

Abstract: Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-( ... ...

Abstract	Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells). In female rat femur, ovariectomy decreased metaphyseal trabecular bone volume (Tb.BV), mineral content (Tb.BMC), yet had no effect on metaphyseal and diaphyseal cortical bone volume (Ct.BV), mineral content (Ct.BMC) and strength parameters (BSPs). In ovaries-intact and ovariectomized rats, oral administration of KY-273 (10 mg/kg/d) for 6 weeks increased metaphyseal and diaphyseal Ct.BV, Ct.BMC, and BSPs without affecting medullary volume (Med.V), but did not affect Tb.BV and Tb.BMC. In ovariectomized rats, alendronate (3 mg/kg/d) caused marked restoration of Tb.BV, Tb.BMC and structural parameters after ovariectomy, and increased metaphyseal but not diaphyseal Ct.BV, Ct.BMC, and BSPs. In ovaries-intact and ovariectomized rats, by the last week, KY-273 increased bone formation rate/bone surface at the periosteal but not the endocortical side. These findings indicate that KY-273 causes osteogenesis in cortical bone at the periosteal side without reducing Med.V. In conclusion, KY-273 has cortical-bone-selective osteogenic effects by osteoblastogenesis via CDK8/19 inhibition in ovaries-intact and ovariectomized rats, and is an orally active drug candidate for bone diseases such as osteoporosis in monotherapy and combination therapy.
MeSH term(s)	Humans ; Rats ; Female ; Animals ; Osteogenesis ; Bone Density ; Rats, Sprague-Dawley ; X-Ray Microtomography ; Osteoporosis/drug therapy ; Ovariectomy ; Mesenchymal Stem Cells ; Minerals/pharmacology ; Cyclin-Dependent Kinase 8
Chemical Substances	Minerals ; CDK8 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 8 (EC 2.7.11.22)
Language	English
Publishing date	2024-03-20
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b23-00834
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Article: Bioinformatic analysis reveals potential relationship between chondrocyte senescence and protein glycosylation in osteoarthritis pathogenesis.

Yoshimoto, Makoto / Sadamori, Koki / Tokumura, Kazuya / Tanaka, Yuki / Fukasawa, Kazuya / Hinoi, Eiichi

Frontiers in endocrinology

2023 Volume 14, Page(s) 1153689

Abstract: Osteoarthritis (OA) is the most common degenerative and progressive joint disease. Cellular senescence is an irreversible cell cycle arrest progressive with age, while protein glycosylation is the most abundant post-translational modification, regulating ...

Abstract	Osteoarthritis (OA) is the most common degenerative and progressive joint disease. Cellular senescence is an irreversible cell cycle arrest progressive with age, while protein glycosylation is the most abundant post-translational modification, regulating various cellular and biological pathways. The implication of either chondrocyte senescence or protein glycosylation in the OA pathogenesis has been extensively and individually studied. In this study, we aimed to investigate the possible relationship between chondrocyte senescence and protein glycosylation on the pathogenesis of OA using single-cell RNA sequencing datasets of clinical OA specimens deposited in the Gene Expression Omnibus database with a different cohort. We demonstrated that both cellular senescence signal and protein glycosylation pathways in chondrocytes are validly associated with OA pathogenesis. In addition, the cellular senescence signal is well-connected to the O-linked glycosylation pathway in OA chondrocyte and vice-versa. The expression levels of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family, which is essential for the biosynthesis of O-Glycans at the early stage, are highly upregulated in OA chondrocytes. Moreover, the expression levels of the GALNT family are prominently associated with chondrocyte senescence as well as pathological features of OA. Collectively, these findings uncover a crucial relationship between chondrocyte senescence and O-linked glycosylation on the OA pathophysiology, thereby revealing a potential target for OA.
MeSH term(s)	Humans ; Chondrocytes/metabolism ; Glycosylation ; Osteoarthritis/genetics ; Osteoarthritis/metabolism ; Cellular Senescence/genetics ; Protein Processing, Post-Translational
Language	English
Publishing date	2023-05-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1153689
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Article ; Online: [Regulation of osteoclastogenesis by osteocytes through growth differentiation factor-15].

Hinoi, Eiichi

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2014 Volume 134, Issue 12, Page(s) 1259–1263

Abstract: Osteocytes are the most abundant cells in bone. However, little attention has been paid to their role in bone remodeling. In this study, osteoclast differentiation was significantly enhanced by conditioned media derived from cultures of osteocytic MLO-Y4 ...

Abstract	Osteocytes are the most abundant cells in bone. However, little attention has been paid to their role in bone remodeling. In this study, osteoclast differentiation was significantly enhanced by conditioned media derived from cultures of osteocytic MLO-Y4 cells that were cultured under hypoxic conditions. Using microarray analysis, we identified growth differentiation factor-15 (GDF15) as a pivotal factor secreted from osteocytes under hypoxia. Indeed, treatment with recombinant GDF15 markedly increased osteoclast differentiation in vitro. Further to investigate the importance of GDF15 in vivo, we used a hypoxic murine model that involved ligation of the right femoral artery. The volume of cancellous bone in the proximal tibia of the ligated limb was significantly reduced, together with a significant increase in osteoclast-related parameters. Addition of anti-GDF15 antibody prevented bone loss and osteoclastic activation in the tibiae of mice that had undergone femoral artery ligation. These results suggest that GDF15, which is secreted from osteocytes under hypoxia during bone remodeling, may be a positive regulator of osteoclastic differentiation. The in vivo usefulness of the anti-GDF15 antibody might provide insights for the development of novel therapeutics for bone disorders related to hypoxia or ischemic insults.
MeSH term(s)	Animals ; Cell Differentiation ; Growth Differentiation Factor 15/metabolism ; Osteoclasts/cytology ; Osteoclasts/metabolism ; Osteocytes/cytology ; Osteocytes/metabolism ; Osteogenesis
Chemical Substances	Growth Differentiation Factor 15
Language	Japanese
Publishing date	2014-11-07
Publishing country	Japan
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.14-00209-4
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Article: [Regulatory mechanism of glycolipid metabolism by bone tissue].

Hinoi, Eiichi

Nihon yakurigaku zasshi. Folia pharmacologica Japonica

2012 Volume 140, Issue 2, Page(s) 96

MeSH term(s)	Animals ; Bone and Bones/physiology ; Glycolipids/metabolism ; Humans ; Insulin/metabolism ; Insulin Secretion ; Osteocalcin/physiology ; Receptors, Adrenergic, beta-2/physiology
Chemical Substances	Glycolipids ; Insulin ; Receptors, Adrenergic, beta-2 ; Osteocalcin (104982-03-8)
Language	Japanese
Publishing date	2012-11-07
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1097532-9
ISSN	1347-8397 ; 0015-5691
ISSN (online)	1347-8397
ISSN	0015-5691
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Article: [Elucidation of signal response mechanisms in bone-related cell lineages].

Hinoi, Eiichi

Nihon yakurigaku zasshi. Folia pharmacologica Japonica

2011 Volume 140, Issue 1, Page(s) 3–7

MeSH term(s)	Animals ; Biological Clocks/genetics ; Biological Clocks/physiology ; Bone and Bones/cytology ; Bone and Bones/physiology ; Cell Lineage ; Chondrocytes/physiology ; Endocrine System/physiology ; Humans ; Neurosecretory Systems/physiology ; Osteoblasts/physiology ; Osteoclasts/physiology ; Oxidative Stress/physiology ; Signal Transduction/physiology
Language	Japanese
Publishing date	2011-03-28
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1097532-9
ISSN	1347-8397 ; 0015-5691
ISSN (online)	1347-8397
ISSN	0015-5691
DOI	10.1254/fpj.140.3
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Article ; Online: Amelioration of Osteoarthritis Development by Daily Oral Supplementation of Royal Jelly.

Lyu, Jiajun / Kubo, Takuya / Iwahashi, Sayuki / Fukasawa, Kazuya / Horie, Tetsuhiro / Nagamatsu, Katashi / Ikeno, Kumiko / Nakamura, Genjiro / Kamakura, Masaki / Hinoi, Eiichi

Biological & pharmaceutical bulletin

2023 Volume 46, Issue 2, Page(s) 348–353

Abstract: Royal jelly (RJ), an essential food for the queen honeybee, has a variety of biological activities. Although RJ exerts preventive effects on various lifestyle-related diseases, such as osteoporosis and obesity, no study evaluated the effect of RJ on the ... ...

Abstract	Royal jelly (RJ), an essential food for the queen honeybee, has a variety of biological activities. Although RJ exerts preventive effects on various lifestyle-related diseases, such as osteoporosis and obesity, no study evaluated the effect of RJ on the development of osteoarthritis (OA), the most common degenerative joint disease. Here, we showed that daily oral administration of raw RJ significantly prevented OA development in vivo following surgically-induced knee joint instability in mice. Furthermore, in vitro experiments using chondrocytes, revealed that raw RJ significantly reduced the expression of inflammatory cytokines and enzymes critical for the degradation of the extracellular matrix (ECM). Similar results were observed after treatment with 10-hydroxy-2-decenoic acid, the most abundant and unique fatty acid in raw RJ. Our results suggest that oral supplementation with RJ would benefit the maintenance of joint health and prophylaxis against OA, possibly by suppressing the activity of inflammatory cytokines and ECM-degrading enzymes.
MeSH term(s)	Animals ; Bees ; Mice ; Fatty Acids/therapeutic use ; Fatty Acids/pharmacology ; Cytokines/metabolism ; Osteoarthritis/drug therapy ; Osteoarthritis/prevention & control ; Dietary Supplements
Chemical Substances	royal jelly (L497I37F0C) ; Fatty Acids ; Cytokines
Language	English
Publishing date	2023-02-01
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b22-00654
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Article ; Online: Osteogenic Effects of KY-054, a Novel Coumarin Derivative on Femur Cortical Bone in Ovariectomized Female Rats.

Yamamoto, Megumi / Ito, Yuma / Fukui, Masaki / Otake, Kazuya / Shoji, Yoshimichi / Kitao, Tatsuya / Shirahase, Hiroaki / Hinoi, Eiichi

Biological & pharmaceutical bulletin

2023 Volume 46, Issue 10, Page(s) 1435–1443

Abstract: Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, ...

Abstract	Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, a 4,6-substituted coumarin derivative, and found that it potently promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity at 0.01-1 µM in mouse-derived mesenchymal stem cells (ST2 cells) and rat bone marrow-derived mesenchymal stem cells (BMSCs). In the ovariectomized (OVX) rats, KY-054 (10 mg/kg/d, 8 weeks) increased plasma bone-type ALP activity, suggesting in vivo promoting effects on osteoblast differentiation and/or activation. In dual-energy X-ray absorption (DEXA) scanning, KY-054 significantly increased the distal and diaphyseal femurs areal bone mineral density (aBMD) that was decreased by ovariectomy, indicating its beneficial effects on bone mineral contents (BMC) and/or bone volume (BV). In micro-computed tomography (micro-CT) scanning, KY-054 had no effect on metaphysis trabecular bone loss and microarchitecture parameters weakened by ovariectomy, but instead increased metaphysis and diaphysis cortical bone volume (Ct.BV) and cortical BMC (Ct.BMC) without reducing medullary volume (Med.V), resulting in increased bone strength parameters. It is concluded that KY-054 preferentially promotes metaphysis and diaphysis cortical bone osteogenesis with little effect on metaphysis trabecular bone resorption, and is a potential orally active osteogenic anti-osteoporosis drug candidate.
MeSH term(s)	Rats ; Female ; Animals ; Mice ; Humans ; Osteogenesis ; X-Ray Microtomography ; Bone and Bones ; Bone Density ; Femur ; Osteoporosis/drug therapy ; Cortical Bone ; Ovariectomy
Language	English
Publishing date	2023-09-16
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b23-00324
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Article ; Online: [Pivotal role of skeletal tissues in the regulation mechanisms for physiological functions mediated by multiple organ networks].

Hinoi, Eiichi

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2011 Volume 132, Issue 6, Page(s) 721–725

Abstract: Bone formation and maintenance are sophisticatedly orchestrated through a well-organized and highly regulated mechanism by two distinct cell types; bone-forming osteoblast and bone-resorbing osteoclast. It has been previously established that the ... ...

Abstract	Bone formation and maintenance are sophisticatedly orchestrated through a well-organized and highly regulated mechanism by two distinct cell types; bone-forming osteoblast and bone-resorbing osteoclast. It has been previously established that the adipocyte-derived hormone leptin regulates bone metabolism through the central nervous system and the sympathetic nervous system. We recently identified the osteoblast as the principal cell type in which the sympathetic tone could signal to regulate bone mass by generating and analyzing the cell specific adrenergic receptor deletion mice. The fact that adipocyte-derived hormone regulates bone metabolism implies that the skeleton might exert a feedback control of glucose metabolism. We then revealed that the skeleton acts as an endocrine regulator of energy metabolism through the osteoblast-specific secreted molecule osteocalcin that activates insulin secretion by pancreatic β-cells, insulin sensitivity in fat, liver, and muscle. Moreover, we have recently reported that the sympathetic tone into osteoblast is a pivotal mediator of leptin regulation of insulin secretion by regulating osteocalcin bioactivity. This unexpected functional cross talk between fat, nervous systems, and skeleton illustrates the importance of the skeleton for the regulation of major physiological functions such as glucose homeostasis in vertebrates.
MeSH term(s)	Adipocytes ; Adipose Tissue/metabolism ; Animals ; Bone Remodeling/physiology ; Bone and Bones/metabolism ; Bone and Bones/physiology ; Central Nervous System/physiology ; Energy Metabolism ; Glucose/metabolism ; Glycolipids/metabolism ; Homeostasis ; Humans ; Insulin/metabolism ; Insulin Secretion ; Leptin/physiology ; Liver/metabolism ; Mice ; Muscles/metabolism ; Osteoblasts/physiology ; Osteocalcin/physiology ; Osteoclasts/physiology ; Receptors, Adrenergic/physiology ; Sympathetic Nervous System/physiology
Chemical Substances	Glycolipids ; Insulin ; Leptin ; Receptors, Adrenergic ; Osteocalcin (104982-03-8) ; Glucose (IY9XDZ35W2)
Language	Japanese
Publishing date	2011-09-29
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.132.721
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